Cirrhosis Hampers Early and Rapid Normalization of Natural Killer Cell Phenotype and Function in Hepatitis C Patients Undergoing Interferon-Free Therapy

Abstract

Background: Chronic hepatitis C virus (HCV) infection impairs natural killer (NK) cell phenotype and function. Whether restoration of NK cells occurs after successful interferon (IFN)-free therapies remains a controversial issue. Aim: To analyze how HCV-related liver cirrhosis impacts changes in NK cells prior and post-IFN-free therapies. Methods: NK cell analysis by multicolor flow cytometry was performed in HCV-infected patients with (n = 17) and without (n = 14) cirrhosis at baseline, week 4 during therapy, and weeks 12 and 48 after the end of therapy (FU12 and FU48, respectively). Non-HCV cirrhotic patients (n = 12) and healthy individuals (n = 12) served as controls. Results: At baseline, HCV cirrhotic patients presented an altered distribution of NK subsets (CD56 dim and CD56 bright) with higher expression of NKp46, HLA-DR, NKp30, KIR2DL2/L3, NKG2A, and CD85j receptors compared to healthy controls. All frequencies normalized by FU48, except for CD85j + cells. Likewise, substantial alterations were detected in NK cell function assessed by (i) signal transducer and activator of transcription 1 (STAT1) and phosphorylated levels of STAT1 and STAT4, (ii) degranulation (CD107a), (iii) cytotoxicity [tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)], and (iv) cytokine production [IFN-γ and tumor necrosis factor-α (TNF-α)]. Of note, NK cell function at FU48 remained partially impaired. In contrast, non-cirrhotics showed normal baseline frequencies of HLA-DR-, NKG2A-, and CD85j-expressing NK cells. Importantly, altered baseline frequencies of NK cell subsets and NKp46 + CD56 dim cells, as well as NK cell function, were rapidly and completely restored. Conclusions: NK cell phenotype alterations persist after HCV eradication in cirrhotic patients, while their function is only partially restored, compromising immune restoration and immunosurveillance.

Chronic genotype 1 hepatitis C along with cirrhosis drives a persistent imprint in virus‐specific CD8+ T cells after direct‐acting antiviral therapies

“…Moreover, any conclusion in relation to clinical outcomes should also take into consideration the innate immune responses. In this regard, we have recently shown that NK cell phenotype alterations persist after HCV eradication in cirrhotic patients, while their function is only partially restored, compromising immune restoration and immunosurveillance 45 …”

“…In this regard, we have recently shown that NK cell phenotype alterations persist after HCV eradication in cirrhotic patients, while their function is only partially restored, compromising immune restoration and immunosurveillance. 45 We acknowledge that our study has limitations. Known cell populations accumulate in the liver during chronic hepatitis C infection.…”

Viral Hepatitis and Hepatocellular Carcinoma: State of the Art

“…However, numerous studies have reported reduced numbers/decreased functionality of NK cells in HCC patients including those associated with HCV infection [69,89,97,102,103]. As with cytotoxic CD8 T cells discussed above, defects in NK cells within the context of HCV and HCC have been reported, particularly their apparent exhaustion and diminished numbers as the stage of disease progresses [72,104]. NK cells produce less granzyme B and perforin as well as reduce their surface expression of NKG2D further limiting their effectiveness at tumor cell clearance [105].…”

Gender as a factor affecting NK cell activity in patients successfully treated for chronic hepatitis C with direct-acting antivirals

“…Chronic hepatitis C (CHC) does not lead to increased activation of NK cells; however, CHC has been shown to dysregulate NK cell functionality [4]. The expression of particular activating and inhibiting receptors on NK cells is distorted; nevertheless, authors have reported various results of their studies [5][6][7][8][9][10][11][12][13][14][15][16][17].…”